Biomedical subjects
Publications and source records attributed to J J Godfroid.
Adding 3-hydroxymethyl N-methyl piperidine (4-chlorophenoxy) acetate, A, at increasing doses in the incubation medium leads to an increase in glycerol release from white adipocytes or brown adipose tissue. This stimulation is dose-dependent and optimal with 10(-6) M.
The 3-hydroxyméthyl N-méthyl piperidine 4-chlorophenoxyacetate, hydrochloride, A, a potent anorectic, reduces weight gain of gold thioglucose obese mice through a reduced body fat and a decrease in metabolic efficiency. Compound A has much less effect in the lean mice than in the obese models. In contrast with pair-fed obese or lean mice, the decreased food consumption cannot account for all the reduced weight gain of the obese controls. Basal lipolytic activity in parametrial adipose tissue is greater in obese mice treated with A then in controls. It seems that the stimulating effect of A on lipolysis could contribute to the weight reduction.
Two products without phosphoryl groups, 1-O-octadecyl-2-O-acetyl-3-O-[gamma-(dimethylamino)propyl]glycerol and its quaternary salt, were synthesized from 1-O-octadecyl-2-O-benzylglycerol. In comparison with PAF-acether, they lost aggregating and bronchoconstrictive activities and did not show any antagonistic effects.
The (4-chlorophenoxyacetate) N-methyl 3-hydroxymethyl piperidine, hydrochloride (PM 170), chemically unrelated to amphetamine, was studied in normal rats for any thermogenic effect. It was given in graded doses. After an acute treatment PM 170 increases energy expenditure by increasing resting oxygen consumption (VO2) and in the doses used, produced dose-related increases in VO2. Energy expenditure of rats treated for 16 days was chronically elevated, while body weight gain and food intake were reduced. It also stimulated mitochondrial oxygen consumption probably by partial uncoupling of respiration from ATP synthesis. The disruption of oxidative phosphorylation could partially explain the effect of this compound on resting metabolic rate.
When chronically administered, 3-hydroxymethyl N-methyl piperidine (4-chlorophenoxy) acetate, hydrochloride, causes reduced food intake and weight gain in obese (fa/fa) rats. We observe an increase in free fatty acid concentration of obese (fa/fa) rats treated for 12 days.
The 3-hydroxymethyl N-methyl piperidine (4-chlorophenoxy) acetate, hydrochloride, A, has been tested for its effect on feeding behavior. This first non-amphetamine substance, with low toxicity and without psychotropic activity, affects the satiety center by reducing gold thioglucose-induced obesity in mice.
3H-labelling of 1-3H-PAF-aceter was prepared by catalytic reduction of 1-O-(9,10)-octadecenyl-2-O-benzyl-sn-glyceryl-3-phosphorylcholine and then acetylated. 5 mumoles of this dehydro derivative dissolved in methanol was treated during 4 hours with tritium gas (80 Ci) and compressed until 1.1 bar by an automatic tritium transfer unit [1]. The catalyst was removed by filtration over Millex (Millipore) and labile tritium atoms eliminated by rotatory flash evaporation. The chemical purity was checked by 3H scanning and autoradiography. It was finally recovered through preparative thin-layer chromatography and then acetylated. The specific radioactivity was found to be close to 40-50 Ci/mmole.
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A new method of synthesis of octadecyl platelet-activating factor (PAF; 1-O-octadecyl 2-O-acetyl sn-glycero-3-phosphorylcholine) is described. Its advantage is to proceed by way of the 'lyso-PAF' which may be substituted by various groups, while avoiding the inconveniences of the total synthesis already described. Moreover, the intermediates in synthesis are easier to purify, with better yields. The platelet-aggregating activity of synthetic PAF, is enantiomer (3-O-octadecyl) and racemic mixtures were 2.7 . 10(-10), 1.7 . 10(-7) and 2.2 . 10(-10) M, respectively. These results indicate the stereospecificity of platelet activation induced by PAF.
Platelet-activating factor (PAF-acether), a mediator of anaphylaxis and inflammation, is a 1-O-alkyl-2-O-acetyl-sn-glyceryl-3-phosphorylcholine. Some analogs of PAF-acether were prepared by total synthesis or by partial synthesis from commercially available phospholipids and tested for platelet aggregating activity. This study indicated that the ether linkage at the position 1 of sn-glycerol and the short acyl chain at position 2 are structural features required for biological activity.
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The synthesis and physicochemical properties of a series of N-[N',N'-disubstituted-amino)acetyl]arylamines are described. A QSAR method is applied to local anesthetic activity and acute toxicity by means of a "nonclassic" substituent variation involving a modification on both aryl and amino moieties. The choice of the different parameters (partition coefficient, pKa, connectivity index, molar refraction, and molar volume) is discussed and their different methods of determination are described. Molar refraction is the parameter which explains best the variance of the local anesthetic activity, and the quadratic regression with MR leads to a "posteriori" synthesis of one compound with optimized activity. However, the partition coefficient is the most explicative parameter for intravenous toxicity.
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The dynamic structure of dicoumarols substituted on the methylene bridge has been studied by nuclear magnetic resonance (nmr) spectroscopy. These molecules may be considered as dimers with restricted rotation around the methylene bridge, held by intramolecular hydrogen bonds; the presence of the substituent R modifies this dynamic process, mainly the facility of exchange of the two hydroxyl protons. These compounds have been compared in respect to their potency in uncoupling oxidative phosphorylation in pig heart mitochondria; the data have been correlated with constants used to characterize the substituent R; to make a potent uncoupler, R should be as small and as hydrophilic as possible. These results are discussed in consonance with the postulated mechanisms of action of the uncouplers, but no simple conclusion can be drawn, especially concerning the role of the dissociable protons.
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The synthesis of new ketophosphonate isosteres of biosynthetic precursors of ether glycerophospholipids resistant to phospholipase C is described following two routes depending on whether the alkoxy chain is introduced before or after the phosphonic moiety. The common intermediates are ketophosphonic acids: better yields were obtained by attaching the n-octadecyl chain to epichlorohydrin, opening and oxidation, blockage of the resulting ketone as the chlorohydrazone, followed by an Arbuzov reaction or by azoene formation and Michael addition. These ketophosphonates differing in chain length in position 3 exhibit potent agonistic activities on rabbit platelets which increase with the number of methylene groups between the phosphonate and the ammonium moieties.
Three-dimensional electrostatic maps were calculated for six potent antagonists of platelet-activating factor (PAF), the antagonists being selected for their apparent structural heterogeneity. The molecules examined were the compact Ginkgolides BN 52020, BN 52021 and BN 52022 (1, 2 and 3), the semi-rigid kadsurenone (4), a flexible synthetic dinor type C furanoid lignan L-652,731 (5a) and the triazolothienobenzodiazepine WEB 2086 (7). Calculation of the electrostatic potential generated around all the above molecules showed the existence of two wells of negative potential or 'cache-oreilles' (ear-muffs), i.e., the isocontours drawn at -10 kcal/mol, located at 180 degrees from each other and separated by a maximum distance of 22-27 A. Except for the synthetic dinor type C furanoid lignan (5a), the molecules also presented a moderate hydrophobic fragment, which constitutes a third point of interaction with the high-affinity binding site in rabbit and human platelets. The findings of the present study allow speculation that this high-affinity acceptor site may be a 'polarized cylinder' with a diameter of 10-12 A.